Impact of adolescent obesity on middle-age health of women given data MAR

We analyze adolescent BMI and middle-age systolic blood pressure (SBP) repeatedly measured on women enrolled in the Fels Longitudinal Study (FLS) between 1929 and 2010 to address three questions: Do adolescent-specific growth rates in body mass index (BMI) and menarche affect middle-age SBP? Do they moderate the aging effect on middle-age SBP? Have the effects changed over historical time? To address the questions, we propose analyzing a growth curve model (GCM) that controls for age, birth-year cohort, and historical time. However, several complications in the data make the GCM analysis nonstandard. First, the person-specific adolescent BMI and middle-age SBP trajectories are unobservable. Second, missing data are substantial on BMI, SBP, and menarche. Finally, modeling the latent trajectories for BMI and SBP, repeatedly measured on two distinct sets of unbalanced time points, are computationally intensive. We adopt a bivariate GCM for BMI and SBP with correlated random coefficients. To efficiently handle missing values of BMI, SBP, and menarche assumed missing at random, we estimate their joint distribution by maximum likelihood via the EM algorithm where the correlated random coefficients and menarche are multivariate normal. The estimated distribution will be transformed to the desired GCM for SBP that includes the random coefficients of BMI and menarche as covariates. We demonstrate unbiased estimation by simulation. We find that adolescent growth rates in BMI and menarche are positively associated with, and moderate, the aging effect on SBP in middle age, controlling for age, cohort, and historical time, but the effect sizes are at most modest. The aging effect is significant on SBP, controlling for cohort and historical time, but not vice versa.     

Tle4 Regulates Epigenetic Silencing of Gamma Interferon Expression during Effector T Helper Cell Tolerance

In response to suboptimal activation, T cells become hyporesponsive, with a severely reduced capacity to proliferate and produce cytokines upon reencounter with antigen. Chromatin analysis of T cells made tolerant by use of different in vitro and in vivo approaches reveals that the expression of gamma interferon (IFN-γ) is epigenetically silenced in anergic effector TH1 cells. In those T cells, calcium signaling triggers the expression of Tle4, a member of the Groucho family of corepressors, which is then recruited to a distal regulatory element in the Ifng locus and causes the establishment of repressive epigenetic marks at the Ifng gene regulatory elements. Consequently, impaired Tle4 activity results in a markedly reduced capacity to inhibit IFN-γ production in tolerized T cells. We propose that Blimp1-dependent recruitment of Tle4 to the Ifng locus causes epigenetic silencing of the expression of the Ifng gene in anergic TH1 cells. These results define a novel function of Groucho family corepressors in peripheral T cells and demonstrate that specific mechanisms are activated in tolerant T helper cells to directly repress expression of effector cytokines, supporting the hypothesis that stable epigenetic imprinting contributes to the maintenance of the tolerance-associated hyporesponsive phenotype in T cells.     

Double-mixing kinetic studies of the reactions of methyl isocyanide and CO with diliganded intermediates of hemoglobin: alpha 2CO beta 2 and alpha 2 beta 2CO

Kinetics of the reactions of CO and methyl isocyanide with two diliganded intermediates of hemoglobin, alpha 2CO beta 2 and alpha 2 beta 2CO, have been studied by double-mixing and microperoxidase methods. The valency hybrids were prepared by high-pressure liquid chromatography. The reaction time courses of ligand combination and dissociation with both of the ligands were biphasic, and in CO combination reaction the zero-time amplitudes of the two phases were independent of the protein concentration. In the presence of 2 M urea the reaction time course was clearly dependent on protein concentration, as the zero-time amplitude of the fast phase increased at lower protein concentrations. These two observations indicate that little dissociation of tetramers into dimers occurs in the absence of urea. Consistent with this, the kinetic data for the reactions of CO best fit a reaction model consisting of two tetrameric species not in rapid equilibrium with each other. Various considerations, however, suggest that the reaction model is more appropriately described as 2D in equilibrium R in equilibrium T. The reaction of triliganded species (Hb4(CO)2Me1) with methyl isocyanide was monophasic, and the reaction model suggested a fast T in equilibrium R structural change after the binding of the third ligand. Although the precise structural nature of the two species remains undefined, it is concluded that the biphasicity in the reactions of the two hybrids is characteristic of the diliganded species only and is independent of the nature of the ligand.     

Sialoglycans in protozoal diseases: Their detection, modes of acquisition and emerging biological roles

Protozoan parasites including Plasmodia, Leishmania, Trypanosoma, Entamoeba, Trichomonas and others cause diseases in humans and domestic livestock having far-reaching socio-economic implications. They show remarkable propensity to survive within hostile environments encountered during their life cycle, and the identification of molecules that enable them to survive in such milieu is a subject of intense research. Currently available knowledge of the parasite cell surface architecture and biochemistry indicates that sialic acid and its principle derivatives are major components of the glycocalyx and assist the parasite to interact with its external environment through functions ranging from parasite survival, infectivity and host-cell recognition. This review highlights the present state of knowledge with regard to parasite sialobiology with an emphasis on its mode(s) of acquisition and their emerging biological roles, notably as an anti-recognition molecule thereby aiding the pathogen to evade host defense mechanisms. Published in 2004. This revised version was published online in August 2006 with corrections to the Cover Date.